Abstract Alzheimer's disease (AD) is the most common form of dementia. It currently affects 5 million people in the U.S., a number that is expected to rise to a staggering 16 million by 2050. AD not only deprives patients of their basic mental functions, but severely batters families and caregivers. Its annual costs are currently estimated at $236 billion, and will likely increase to more than $1 trillion by 2050. As our society rapidly ages, the need to combat AD grows increasingly pressing. Histological and imaging studies in AD patients and animal models have shown that the entorhinal cortex is a primary site of atrophy and activity loss in the early phases of AD. Inside the entorhinal cortex, neurons in layer II are known to undergo earliest neurodegeneration. However, it is still largely unclear what cell type in layer II of the entorhinal cortex exhibits such neurodegeneration. Our preliminary results and recent literature suggest a possibility that layer II neurons show cell-type-specific vulnerability to neurodegeneration. Here we propose studies to characterize the cell-type-specific neurodegeneration of layer II neurons in the entorhinal cortex, and to investigate the circuit mechanisms by which cell-type-specific cell death causes memory impairment in AD. Our approach involves cell-type-specific histological analyses, cell-type- specific in vivo recording of spike activity, cell-type-specific optogenetic and chemogenetic methods, and a novel APP knock-in mouse model. There are three Specific Aims: (Aim 1) To identify histological and molecular properties of degenerating entorhinal cortex neuronal types in APP-KI mice; (Aim 2) To identify in vivo electrophysiological spike activities of entorhinal cortex cell types; and (Aim 3) To determine the effect of entorhinal neurodegeneration on hippocampal place cell activity and on memory loss of APP knock-in mice. If successful, our studies will identify cellular and circuit mechanisms of cell-type-specific neurodegeneration in the entorhinal cortex in AD. Such knowledge of entorhinal cell-type-specific vulnerability is expected to be a breakthrough for future identification of therapeutic targets to prevent or slow AD progression.